1. Technical Field
The present invention relates to a novel composition which is particularly useful as an ophthalmic irrigation solution which may be used in ocular surgery, although other uses, for example, ophthalmic topical application and surgeries in general, are also contemplated.
2. Background Information
An ophthalmic irrigation solution is used for the application on the external surface of the eyes topically and in ocular surgeries to rinse, as well as to keep the operated ocular tissues moist. Replacement of the aqueous and/or vitreous humors with the irrigation solution occurs as the consequence of ocular surgeries including corneal transplant (penetrating keratoplasty), cataract extraction, intraocular lens implantation and vitrectomy. In these instances, the irrigation solution remains in the eyes after surgery until the components are either deprived by the surrounding tissues or the solution is eventually equilibrated with body fluids, with subsequent clearance through the circulation. Thus, the irrigation solution used should not only be physiologically compatible, including tonicity and pH, but it should also contain components enabling the cells to sustain their viability and capability to perform physiological functions, at least until a full equilibration of the anterior chamber and the vitreous with the physiological body fluids is reached.
The irrigation solution is of particular importance to the cornea and the lens. Both organs are avascular. The cornea obtains its nourishment mainly from the fluid in the anterior chamber, and to a lesser extent, from the tear. The lens obtains its nourishment from fluids, both in the anterior chamber and in the vitreous. The retina, ciliary body and iris are vascularized tissues; they obtain their nourishment through the circulating plasma of the blood vessel network. Therefore, the components of the irrigation solution may not exert an effect on these tissues as significant as that on the cornea and the lens.
In the cornea, the monolayer endothelium lining the posterior surface contains ion transport sites which help maintain the cornea deturgescense and thereby the transparency. In the lens, the ion transport sites are located in the epithelium underneath the capsule. In general, the Na.sup.+ -K.sup.+ ATPase is located in the cytoplasmic membrane which helps maintain cellular Na.sup.+ and K.sup.+ contents at approximately 10 and 100 mM, respectively, and facilitates the transport against the extracellular salt concentration gradients of about 120 mM Na.sup.+ and 10 mM K.sup.+. Adequate energy is needed for the cells (and tissues) to perform the ion transport activity.
Glucose is the major energy source for mammalian cells. The cornea, lens and retina are very active glycolysing tissues which utilize glucose and produce lactic acid, even under aerobic conditions. When the isolated cornea is stored in a medium containing glucose, excess lactic acid is formed and accumulated, resulting in an acidity that subsequently inhibits the metabolic activity of the tissue. In vivo, lactic acid formed in the vascularized tissue is cleared through the circulation, whereas that formed in the avascular cornea and lens is released into the anterior chamber and removed via the clearance mechanism of the circulation. In humans, lactic acid in the anterior chamber is maintained at a steady, low level of approximately 4.0 to 4.5 mM.
Glucose is an important and useful energy source for ocular tissues when it is present in an irrigation solution for in vivo application. Utilization of glucose via glycolysis produces ATP at a high rate and is independent of O.sub.2 ; however, it is not an effective energy-generating pathway, as only 2 moles of ATP are formed per mole of glucose utilized. Two moles of lactic acid are also formed. When the clearance mechanism of the operated ocular tissues is not sufficiently effective, lactic acid will be accumulated, resulting in a lower pH which, in turn, inhibits the metabolic activity of the tissues. In contrast, in tissues with a high mitochondrial population, a complete oxidation of glucose to CO.sub.2 and H.sub.2 O may occur, via mitochondria, generating as much as 38 moles of ATP per mole of glucose utilized, including the oxidation of two moles of NADH formed in the glycolysis. Therefore, it is evident that utilization of substrates via oxidation in mitochondria is an effective energy-generating pathway when oxygen is available. Under this condition, there is no lactic acid accumulation. In addition, lactic acid accumulation may be diminished or minimized when anaerobic glycolysis is inhibited by an enhanced respiration via the Pasteur effect.
Glucose cannot be used directly as a substrate in the mitochondria; it has to be converted first to pyruvate via glycolysis. Ketone bodies (a collective term for acetone, acetoacetate and .beta.-hydroxybutyrate) and precursors thereof (such as short chain fatty acids and ketogenic amino acids) are readily oxidized in the mitochondria, producing 32 molecules of ATP per acetyl moiety utilized. Therefore, ketone bodies and precursors thereof are energy-rich or energy-efficient molecules. Furthermore, oxidation of ketone bodies and precursors thereof results in an enhanced respiration which, in turn, inhibits anaerobic glycolysis via the Pasteur effect. In humans and most other mammals, ketone bodies are formed in the liver from oxidation of fatty acids and ketogenic amino acids (including leucine, lysine, phenylalanine, tyrosine and tryptophan). Ketone bodies are not oxidized further in the liver but are transported by the circulating blood to the peripheral tissues. There they are oxidized to CO.sub.2 and H.sub.2 O via acetyl CoA and citric acid cycle, yielding a rich energy for the peripheral tissues. Ketone bodies are known to be the preferred fuel for the brain, muscle, and kidney during starvation. (R. E. Olson, Nature, 195, 597, 1962; E. Bassenge et al, Am. J. Physiol., 208, 162, 1965; O. E. Owen et al, J. Clin. Invest., 46, 1589, 1967; and R. A. Howkins et al, Biochem. J., 122, 13, 1971 and 125, 541, 1971). Ketone bodies are also utilized in the cornea.
In addition, complete oxidation of ketone bodies and precursors thereof yields CO.sub.2 and H.sub.2 O, with accumulation of no other metabolic wastes. Carbon dioxide formed is subsequently hydrated to form carbonic acid, which is further dissociated to form bicarbonate at pH 7.4. Bicarbonate has been suggested as necessary for the ion transport process across the corneal endothelium (S. Hodson et al., J. Physiol., 263, 563, 1976).
Pathways for the formation of ketone bodies from fatty acids and ketogenic amino acids are illustrated in FIG. 1.